We wish to determine the function of the gene G4.5 in normal heart development. Mutations in G4.5 have recently been found to cause Barth syndrome (BTHS), a cardiomyopathy with growth retardation, neutropenia and abnormal excretion of leucine and isoleucine catabolic intermediates. We hypothesize that the G4.5 proteins are components of a signal transduction pathway leading to the development of normal heart structure, and that there are severe pathological consequences of interrupting this pathway. A second testable hypothesis is that the G4.5 proteins are components of leucine and isoleucine catabolism. It is our primary objective to test these hypotheses. Since on complication of BTHS is congestive heart failure, and since this is a complication of many other more common heart conditions, it is possible that an understanding of BTHS may lead to rational treatment for other heart diseases as well. The funds provided by this agency will allow us to do research and to expose students from traditionally under-represented groups to scientific inquiry. The institutions where work will be done is a comprehensive minority institutions with more than 50% of the student body being American Indian, Chicano, Hispanic, African American, Asian or Pacific Islander, with a total enrollment of approximately 25,000 students. We will be able to provide several students with intense exposure to the rapidly-expanding field of molecular biology. The techniques that will be needed to accomplish this work include amplification of DNA sequences by polymerase chain reaction, electrophoresis of these fragments, and nucleotide sequence determinations. Other techniques that the students may learn in the course of this research include cell culture, confocal microscopy, preparation of DNA, mRNA and cDNA, proteins and antibodies, enzyme assays, and computer database searches and sequence manipulation and analysis. The students will be learning very up-to-date techniques in molecular biology which should serve them well in their careers, with and additional prospect of breaking new ground in the field of developmental genetics. It is a premise of this proposal that it will be possible to produce both substantive research results and highly trained young scientist from ethnic groups traditionally under- represented in the sciences, by focusing attention on the intensive training of just a few students in the fundamentals and the specifics of scientific inquiry, in teaching professionalism by example, and by providing the students with salaries so that they can devote themselves to this work.